The present invention relates to novel pharmaceutical compounds having unique site-specific and site-retention properties. These pharmaceutical compounds are useful in the treatment of a number of medical disorders including infection, pain, menstrual abnormalities, glaucoma and inflammation. In one aspect, the present invention relates to novel anti-inflammatory compounds useful in the treatment of gastrointestinal inflammation. The invention further relates to a method of controlling the delivery of anti-inflammatory compounds, particularly mesalamine (5-amino salicylic acid, 5-ASA), 4-amino salicylic acid (4-ASA), and 3-amino salicylic acid (3-ASA) to the entire gastrointestinal (GI) tract in patients suffering from inflammatory bowel disease. The present invention principally relates to the treatment of inflammatory bowel diseases and functional bowel disorders with anti-inflammatory drugs such as mesalamine (5-ASA). Unlike conventional and well established treatments, which rely on timed-release, bacteria-mediated hydrolysis and/or pH dependent release formulations that have restricted access to gastrointestinally inflamed tissue, the compositions of the present invention can target a site throughout the length of the gastrointestinal intestinal tract to consistently deliver the medicine where it will be clinically most effective.
The ability of mesalamine to reduce inflammation is well established; however, its clinical efficacy for the treatment of certain inflammatory bowel diseases is not compelling because its pharmacological activity is dependent on where the drug is released in the intestinal tract. It is believed that mesalamine inhibits the production of leukotrienes and prostaglandins from arachidonic acid through a local effect at the sites of bowel inflammation; however, pre-clinical and clinical studies with current mesalamine products suggest these formulations have a variable release throughout the intestinal tract and are not retained at the inflammatory sites for a time sufficient to reduce inflammation. Moreover, the differences in the site of drug release (duodenum, jejunum, ileum or colon) from these formulations results in dramatically different absorption and metabolism of the drug. The variations in drug release and drug retention at different locations within the bowel from these commercial formulations makes it particularly difficult to treat patients having locally induced inflammation that differs from the release location.
Treating patients with anti-inflammatory compounds with gastrointestinal inflammation is not new, and the Food and Drug Administration (FDA) has already approved treating patients with mesalamine for certain types of inflammatory bowel disease that occur in the colon, namely ulcerative colitis. A number of different oral or rectal mesalamine formulations are commercially available for the treatment of inflammation in ulcerative colitis; however, each has met with limited success in ameliorating the symptoms of Crohn's disease. The principal difficulties with currently available mesalamine formulations include the inability to consistently release mesalamine at the inflamed tissue in different patients and the inability to locally deliver mesalamine to the site of inflammation for a time effective in reducing inflammation. The latter is due, in part, to extensive absorption and deactivation of mesalamine in the proximal ileum. Ironically, the clinical success of mesalamine formulations in treating inflammation in the colon has fostered the development of additional mesalamine formulations that only release the drug in the colon.
In the treatment of distal colitis, an enema preparation of mesalamine (Rowasa® enema) is considered efficacious. In the initial study to identify the active moiety in sulfasalazine, patients with distal ulcerative colitis were treated with sulfasalazine, mesalamine, or sulfapyridine enemas. Three quarters of the patients in the sulfasalazine and mesalamine groups showed improvement, while only about one third of patients in the sulfapyridine group improved. These data supported the hypothesis that mesalamine was the active therapeutic moiety, and subsequent studies confirmed the efficacy of mesalamine enemas in distal colitis. (Azad Khan et al. Lancet 2:892–895 (1977); Physician's Desk Reference 55th Edition pp 3160–3162, publ. Medical Economics (2001); U.S. Pat. No. 4,496,553).
Mesalamine, rectally administered through an enema, has limited systemic absorption and consequently good topical effectiveness in treating inflammation in the colon; however, rectally administered mesalamine acts only locally on the recto-sigmoidal colon so that more proximal inflammation cannot be treated in this manner. Moreover, patient compliance with rectally administered mesalamine is low, and has been associated with an increase colon cancer. Oral delivery of mesalamine is the preferred route of administration; however, suitable formulations have been elusive. Oral delivery of mesalamine to sites of inflammation located above the transverse colon, and particularly to the proximal small bowel, is more complex and successful delivery and therapeutic benefit depends upon factors such as gastric emptying time and retention time in the intestinal lumen. Gastric emptying time varies from one individual to another and in the same individual may vary according to the size of (orally taken) particles (or tablets) and according to whether the patient is in a fasting or non-fasting state. Dwell time in the ileum is also variable and particularly important in previously surgically treated Crohn's patients having a shortened small bowel. Luminal retention is related to the absorption and metabolism of mesalamine in the upper portion of the small intestine.
Another difficulty in formulating oral mesalamine for accurate targeting is stomach acidity, which destroys the drug preparations before they reach the bowel. The development and commercialization of both enterically coated drug dosage forms and prodrugs resistant to hydrolysis in the stomach have addressed this.
Enterically coated mesalamine dosage forms include Asacol®, Claversal®, and Pentasa®. Asacol® is coated with a delayed release acrylic resin (Eudrogit-S) that releases the drug in the distal ileum and colon. The resin on Asacol® releases mesalamine in a pH-dependent manner at pH 6 or above, causing release of mesalamine in the distal small bowel and colon making this drug ideal for the treatment of ulcerative colitis. Claversal® is also coated with a delayed release acrylic resin (Eudrogit-L) that releases the drug in the distal ileum and colon. Pentasa® contains ethylcellulose-coated, controlled-release microgranules of mesalamine that release mesalamine in a time-release manner throughout the distal portion of the small and the entire large intestine. Accordingly, Pentasa® would appear suitable for the treatment of Crohn's disease when the distal ileum is affected in addition to its use in ulcerative colitis. Each of these formulations uses a different mechanism to deliver the mesalamine to the sites of inflammation such as distal ileum and colon; however, they were all designed to bypass the areas of rapid absorption and inactivation of mesalamine in the duodenum and the jejunum by releasing the drug lower in the small intestine and colon. Innovative approaches in the development of orally administered mesalamine and its attendant problems are illustrated in U.S. Pat. Nos. 4,980,173, 4,496,553, 4,880,794, and 5,010,069; and the review by Prakash, A and Markham, A in Drugs 57(3): 383–408 (1999).
Attempts to overcome this acidity problem have also included use of the prodrugs sulfasalazine (Azulfidine®), olsalazine (Dipentum®) and balasalazide (Colazide®) that resist stomach acidity to yield free 5-ASA after cleavage by bacterial enzymes in the colon. In addition to the reported adverse side effects, accurate targeting of diseased sites with sulfasalazine, olsalazine and balasalazide is limited by the variations in colonic bacterial flora required for bacterial cleavage of these compounds.
The toxic effects of sulfapyridine are the limiting factor in using sulfasalazine. Common adverse reactions include headache, nausea, anorexia, and dyspepsia. These symptoms relate to plasma levels of sulfapyridine and usually occur at dosages greater than 3 g/day. Because of sulfasalazine's substantial toxicity and the limitation of dosing due to side effects, efforts were made to develop mesalamine products with other delivery systems to prevent proximal small bowel absorption.

Initially developed in the 1940s for the treatment of rheumatoid arthritis, salicyl-azo-sulfapyridine, or sulfasalazine was quickly recognized as being efficacious in the treatment of colitis. Consisting of a molecule of 5-aminosalicylic acid (5-ASA) joined by an azo bond to a molecule of sulfapyridine, sulfasalazine had, until recently, been a mainstay in the treatment of ulcerative colitis for more than 50 years. The active moiety in sulfasalazine is 5-ASA, with the sulfapyridine acting as a carrier to prevent absorption of 5-ASA in the small bowel. In the distal ileum and colon, bacteria that possess azoreductase, an enzyme in almost all colonic bacteria, split the molecule, releasing free 5-ASA and sulfapyridine. The sulfapyridine is readily absorbed from the colon, acetylated in the liver, and conjugated with glucuronic acid, and excreted in the urine. The 5-ASA is only minimally absorbed, with the majority being excreted in the feces unchanged. 5-ASA's mechanism of action is by direct contact with colonic mucosa to suppress various pro-inflammatory pathways including both cyclooxygenase and lipoxygenase derived products such as prostaglandins and leukotrienes from arachidonic acid and from suppression of superoxide dismutase.
The two newer versions of the azo-linked prodrugs similar to sulfasalazine are olsalazine and balsalazide whose chemical structures are shown below:

The presence of the azo bond in both of these compounds, similar to sulfasalazine's, prevents small-bowel absorption and allows for delivery of the drug mainly in the colon, where bacterial azo reductase liberates the 5-ASA. These drugs would therefore be useful in the same circumstances as sulfasalazine; however, the 5-ASA products may cause diarrhea due to decreased water absorption in the small bowel, most frequently with olsalazine. Since the diseases these drugs are used to treat are diarrheal illnesses, their use may be limited by this untoward effect.
It is well known that the time of transit of matter in the small intestine is limited to about 3–4 hours, whereas the time of transit in the colon is of the order of 20–70 hours. Therefore, controlled-release systems aiming at delivering specific drugs requiring absorption times of more than 3–4 hours have generally relied on colonic delivery. In addition, mesalamine-based drug formulations have generally been designed to target active drug to the colon so that the drug is not destroyed or inactivated by the stomach nor is it rapidly absorbed and metabolized in the upper intestine. Unfortunately, this approach has severely limited the usefulness of mesalamine if the inflammation is in parts of the gastrointestinal tract are not in proximity to the active drug. It is therefore desirable to provide pharmaceutical compositions capable of delivering mesalamine and other topically active pharmacological agents to an inflamed site throughout the gastrointestinal tract whereby the active agent is brought into direct, topical contact with the inflammation.
Crohn's disease is a chronic inflammatory bowel disease that produces patchy, discontinuous inflammation primarily in the small intestine; however, it can produce inflammation in any part of the digestive tract including the mouth esophagus, stomach and colon. This inflammation extends into all layers of the intestinal tissue resulting in pain, diarrhea, gastrointestinal bleeding and malabsorption of nutrients from foods. If the treatment of the inflammation is unsuccessful, the disease progresses and leads to narrowing (stricture) and blocking (obstruction) of the intestinal lumen, the development of abnormal passageways (fistulas) leading from the intestine to another part of the body, and areas of infection (abscesses). It is advantageous to reduce the inflammation associated with the earliest mucosal lesion of Crohn's disease. The earliest mucosal lesion of Crohn's disease is crypt injury in the form of inflammation (cryptitis) and crypt abscesses, which progress to tiny focal aphthoid ulcers, usually located over nodules of lymphoid tissue. As the inflammatory process evolves, the influx and proliferation of macrophages and other inflammatory cells leads to the formation of granulomas. As the disease progresses further, the transmural spread of inflammation leads to bowel wall thickening, deep ulceration, fistulas and abscesses.
It is therefore an object of the present invention to provide site-specific delivery of mesalamine to the inflamed portions of the gastrointestinal tract regardless of location. It is a further object of the present invention to provide site-specific delivery of mesalamine to the inflamed portions of the gastrointestinal tract in those patients with Crohn's disease and ulcerative colitis. It is a further object of the present invention to provide anti-inflammatory agents that are retained at the areas of inflammation for a time effective in reducing the inflammation.
It is a further object of the invention to provide a controlled delivery system which maintains the inflammatory drugs in the small intestine beyond the normal 3–4 hours transit time and allows the required luminal concentration of these drugs to be maintained for more extended periods. It is a further object of the invention to provide a controlled delivery system that maintains the inflammatory drugs in the small intestine and allows the required luminal concentration of these drugs to be maintained for a period from about 4.0 to about 12.0 hours.
A further object of the invention is to ensure accurate and safe delivery of topically active therapeutic agents such as mesalamine to the duodenal, jejunal or proximal small bowel and other segments of the gastrointestinal tract to allow treatment of severe Crohn's ileitis, duodenitis, jejunitis as well as fulminant ulcerative colitis.
In other aspects, the present invention relates to novel compounds useful in the treatment of a variety of ophthalmic disorders, menstruation and menstrual abnormalities, vaginal disorders, intestinal disorders and pelvic inflammatory diseases in which it is desired to provide therapeutic agents that are retained at the diseased areas for a time effective in treating the disorders. It is therefore a further object of the present invention to provide site-specific delivery of therapeutic agents to the diseased areas of the eye, vagina, uterus, upper genital tract and intestine.